Over the past several years it has become obvious to health professionals and the pharmaceutical industry that optimal therapy with existing drugs has not been achieved with conventional dosage forms (e.g., tablets, capsules, injectables, suppositories) and dosing regimens. The term "optimal therapy" means the safest, most rapid, and most convenient amelioration of any particular disease state. Further, the "safety" of a dosage form or dosing regimen refers to the frequency and severity of side reactions. Improvement in therapy can then be defined as any change in the dosage form or regimen for an existing drug that: (1) reduces the frequency and severity of side reactions, (2) increases the rate at which cure or control is achieved, and (3) decreases the degree of disruption of normal patient activities.
In response to this growing perception, a number of novel drug delivery systems have been developed and brought to market. Some good examples are the transdermal delivery devices such as Nitro-Dur.RTM. (Key Pharmaceuticals), Nitro-Disc.RTM. (Searle), Transderm Nitro.RTM. (Ciba), Clonidine-TSS.RTM. (Boehringer-Ingelheim) and Transderm-Scop.RTM. (Ciba). Other examples are Theo-Dur.RTM. tablets, a sustained release form of theophylline, Theo-Dur Sprinkle.RTM. (U.S. Pat. 4,587,118) and Slo-Bid.RTM.. Theo-Dur Sprinkle.RTM. and Slo-Bid.RTM. are microencapsulated forms of slow release theophylline that are intended for use in pediatric patients or other patients who may have difficulty in swallowing a tablet. The microcapsules are supplied in hard gelatin capsules. The hard gelatin capsules are opened at the point of use by the care-giver and administered in a soft food.
This form of drug delivery has significant drawbacks. First, there are a small finite number of capsule sizes marketed, and this limits the physician's ability to prescribe an appropriate dose on the basis of a particular patient's weight, severity of disease, and therapeutic response. Second, there is the possibility of tampering which has become a subject of major concern related to the safety of over-the-counter pharmaceutical products.
Flowable material dispensers such as that described in U.S. Pat. 4,579,256 were developed to overcome these drawbacks. The Flowable Material Dispenser is an adjustable, metering and dispensing package. The dispenser can accurately deliver a granular pharmaceutical product to a patient by pouring the selected dosage onto a small quantity of soft food contained on a spoon prior to swallowing. The dispenser is child- resistant, protects the product from the surrounding environment and precisely delivers an adjustable dose well within the compendial requirements for uniformity of dosage units. However, microcapsules that are suitable for use in the Flowable Material Dispenser must meet certain narrow specifications with regard to average particle size, particle size distribution, shape and active agent concentration. These specifications are generally defined as follows:
______________________________________ Particle size/size distribution A: 710 Microns-1000 Microns (depending on dispenser B: 590 microns-840 Microns design) C: 500 microns-710 Microns Activity density not less than 0.200 g/ml (potency & bulk density) Appearance nearly spherical Flow freely flowing ______________________________________
Although an acceptable product could be made beyond the limits of these parameters, high potency and small size are required to achieve the necessary bulk density which insures that the largest dose is contained in a volume that is convenient to swallow. Small size is also essential if the particles are to be relatively impalpable when added to soft food. High bulk density allows a dispenser of reasonable size for one hand operation to contain a ten to sixty day supply of drug. Narrow size distribution insures reproducibility of each measured dose and eliminates variation in bulk density due to segregation of sizes. This is critical to a device which measures solid particles by volume. Narrow particle size distribution also implies reproducibility of bulk density from batch to batch. Thus, the same volume will contain the same amount of drug every time in production, which is a new requirement, imposed by the flowable material dispenser but not by prior art delivery systems like hard gelatin capsules. It is also important that the microcapsules be nearly spherical to impart the flow characteristics that are required at every stage of assembly and use of the dispenser. The nearly spherical aspect of the microcapsules also enhances product elegance.
Presently available conventional pharmaceutically active granules are generally inappropriate for oral administration with semi-solid food or for use in a handheld flowable material dispenser. These conventional granules are large and create a noticeable gritty mouthfeel for the patient. Large microgranule size also necessitates an increase in the smallest characteristic dimension of the measuring cylinder, and the flow channels of the flowable material dispenser if particle bridging is to be avoided. An increase in the smallest characteristic dimension of the measuring cylinder is also necessary if the requirements of the U.S. Pharmacopeia for Uniformity of Dosage Units are to be met. As those characteristic dimensions increase, so does the overall size of the flowable material dispenser. Each increase in size of the dispenser results in the loss of a degree of convenience in its use. At some microgranule size larger than 18 mesh (1000 microns), the flowable material dispenser becomes too large to be comfortably hand-held and hand-operated. Conventional granules are also difficult to accurately dispense from a hand-held flowable material dispenser due to the broad size distribution of granules both within and between batches, as well as the lack of uniform shape of the conventional granules.
Additionally, most pharmaceutically active agents have an unpleasant taste, and many such agents are administered to children who have more taste buds on their tongues than adults and are therefore more cognizant of unpleasant tastes (Remington's Pharmaceutical Sciences, 5th ed., p. 1226 (1975)). Some of the pharmaceutically active agents with a more notorious reputation for unpleasant taste include amoxicillin, dicloxicillin, ampicillin, penicillin, erythromycin, cephalosporins and prednisone.
Numerous attempts to mask these unpleasant tastes in conventional dosage forms such as tablets, solutions and suspensions follow the conventional wisdom of attempting to overpower the unpleasant flavor with a more pleasant one. For example, salty tastes are conventionally masked by syrups such as cinnamon syrup, orange syrup and cherry syrup; bitter tastes are conventionally masked by syrups such as cocoa syrup, raspberry syrup and cherry syrup; acrid or sour tastes are conventionally masked by syrups such as raspberry syrup and acacia syrup; and oily tastes are conventionally masked by syrups such as aromatic rhubarb syrup, compound sarsaparilla syrup and lemon syrup. These conventional taste-masking techniques were more often than not less than satisfactory, particularly in the case of children's medicines.
Amoxicillin is uniquely suited for incorporation into a flowable material dispenser because it is well known that dose-related gastrointestinal upsets (epigastric distress, nausea, vomiting, and especially diarrhea) occur commonly with amoxicillin administration. It is this adverse effect that the present invention is intended to eliminate. It is believed that much of the diarrhea that occurs during amoxicillin therapy is due to overdose and that accurate delivery of the appropriate dose by weight in taste-masked form will provide significant therapeutic advantage.